Nardilysin controls intestinal tumorigenesis through HDAC1/p53–dependent transcriptional regulation

Kanda, Keitaro; Sakamoto, Jiro; Matsumoto, Y; Ikuta, Kozo; Goto, Norihiro; Morita, Yusuke; Ohno, Mikiko; Nishi, Kiyoto; Eto, Koji; Kimura, Yuto; Nakanishi, Yuki; Ikegami, Kanako; Yoshikawa, Takaaki; Fukuda, Akira; Kawada, Kenji; Sakai, Yoshiharu; Ito, Akihiro; Yoshida, Minoru; Kimura, Takeshi; Chiba, Tsutomu; Nishi, Eiichiro; Seno, Hiroshi

doi:10.1172/jci.insight.91316

Cited by 10 publications

(9 citation statements)

References 39 publications

(44 reference statements)

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“…Its expression can be inhibited by the methylation inhibitor 5-aza-2′-deoxycytidine, an effect which is further enhanced by histone deacetylase inhibitors (trichostatin A, depsipeptide). The methylation of the HRK promoter significantly correlated with the p53 wildtype status in 58 CRC cases [88].…”

Section: Methylation Status Of P53 Downstream Genesmentioning

confidence: 95%

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Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma

Tomičić

Dawood

Efferth

2021

Cancers

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Colorectal cancer (CRC) belongs to the most common tumor types, and half of all CRC harbor missense mutations in the TP53 tumor suppressor gene. In addition to genetically caused loss of function of p53, epigenetic alterations (DNA methylation, histone modifications, micro-RNAs) contribute to CRC development. In this review, we focused on epigenetic alterations related to the entire p53 signaling pathway upstream and downstream of p53. Methylation of genes which activate p53 function has been reported, and methylation of APC and MGMT was associated with increased mutation rates of TP53. The micro-RNA 34a activates TP53 and was methylated in CRC. Proteins that regulate TP53 DNA methylation, mutations, and acetylation of TP53-related histones were methylated in CRC. P53 regulates the activity of numerous downstream proteins. Even if TP53 is not mutated, the function of wildtype p53 may be compromised if corresponding downstream genes are epigenetically inactivated. Thus, the role of p53 for CRC development, therapy response, and survival prognosis of patients may be much more eminent than previously estimated. Therefore, we propose that novel diagnostic devices measuring the entirety of genetic and epigenetic changes in the “p53 signalome” have the potential to improve the predictive and prognostic power in CRC diagnostics and management.

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Section: Methylation Status Of P53 Downstream Genesmentioning

confidence: 95%

“…In addition to methylation, epigenetic regulation of p53 can also take place by acetylation (Table 3). NRDC is a histone-binding protein that binds HDAC1 and inhibits HDAC1 recruitment to the TP53 promoter and p53 acetylation [87,88].…”

Section: Acetylation Of P53mentioning

confidence: 99%

Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma

Tomičić

Dawood

Efferth

2021

Cancers

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“…Analysis of NRDC‐deficient ( Nrdc −/− ) mice revealed that NRDC critically regulates myelination in the central and peripheral nervous system through the regulation of neuregulin‐1 shedding 20 . In addition to this extracellular function as an enhancer of ectodomain cleavage, NRDC in the nucleus controls transcription as a coregulator of several transcription factors such as peroxisome proliferator‐activated receptor gamma coactivator 1‐alpha (PGC‐1α), 21 islet‐1, 22 and histone deacetylases 23,24 . Moreover, we have recently proposed the possible clinical use of serum NRDC levels as a biomarker for several clinical settings 25‐27 .…”

Section: Introductionmentioning

confidence: 95%

“…19 In addition to this extracellular function as an enhancer of ectodomain cleavage, NRDC in the nucleus controls transcription as a coregulator of several transcription factors such as peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), 20 islet-1, 21 and histone deacetylases. 22,23 Moreover, we have recently proposed the possible clinical use of serum NRDC levels as a biomarker for several clinical settings. [24][25][26] For example, serum NRDC is elevated early after the onset in patients with acute coronary syndrome.…”

Section: Introductionmentioning

confidence: 99%

Nardilysin controls cardiac sympathetic innervation patterning through regulation of p75 neurotrophin receptor

et al. 2020

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Cardiac sympathetic innervation is critically involved in the regulation of circulatory dynamics. However, the molecular mechanism for the innervation patterning has remained elusive. Here, we demonstrate that nardilysin (NRDC, Nrdc), an enhancer of ectodomain shedding, regulates cardiac sympathetic innervation. Nardilysin‐deficient (Nrdc−/−) mice show hypoplastic hearts, hypotension, bradycardia, and abnormal sympathetic innervation patterning. While the innervation of left ventricle (LV) of wild‐type mice is denser in the subepicardium than in the subendocardium, Nrdc−/− LV lacks such a polarity and is uniformly and more abundantly innervated. At the molecular level, the full‐length form of p75 neurotrophin receptor (p75NTR, Ngfr) is increased in Nrdc−/− LV due to the reduced ectodomain shedding of p75NTR. Importantly, the reduction of p75NTR rescued the abnormal innervation phenotype of Nrdc−/− mice. Moreover, sympathetic neuron‐specific, but not cardiomyocyte‐specific deletion of Nrdc recapitulated the abnormal innervation patterning of Nrdc−/− mice. In conclusion, neuronal nardilysin critically regulates cardiac sympathetic innervation and circulatory dynamics via modulation of p75NTR.

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“…19) In vivo, NRDC deficiency in mice showed growth retardation, hypomyelination, hypothermia and glucose intolerance. 18,[20][21][22] Furthermore, NRDC deficiency reduced hepatic fibrosis and inflammation in a dietary-induced non-alcoholic steatohepatitis, 21) as well as gastric cancer progression, metaplasia and inflammation 22,23) and autoimmune arthritis, 24) in mice. NRDC also reduces acetylation of H3K9, increases H3K4me2, and controls cell cycle-related genes.…”

Section: Introductionmentioning

confidence: 97%

Deficiency of Nardilysin in the Liver Reduces Serum Cholesterol Levels

Yasuda

Hiraoka

Ohno

et al. 2021

Biological & Pharmaceutical Bulletin

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Nardilysin (NRDC) has been shown to be involved in post-translational histone modifications, in addition to enhancement in ectodomain shedding of membrane-anchored protein, which play significant roles in various pathophysiology, including glucose homeostasis, inflammatory diseases and cancer. The present study sought to determine roles of NRDC in the liver on lipid and lipoprotein metabolism. We established liver-specific NRDC deficient mice by use of NRD1 floxed mice and albumin promoter-Cre recombinase (Cre) transgenic mice, and found that their serum low-density lipoprotein (LDL) cholesterol levels were significantly lower than those in control littermate mice. In the liver, LDL receptor (LDLR) mRNA expression was significantly upregulated, while inducible degrader of LDLR (IDOL) and microsomal triglyceride transfer protein (MTP) mRNA expression was significantly downregulated, in liver-specific NRDC deficient mice. Hepatic cell-surface LDLR expression levels were significantly elevated and serum pro-protein convertase subtilisin-kexin type 9 (PCSK9) levels were significantly reduced in mice with hepatic NRDC deficiency. In cultured hepatocytes, NRDC deficiency significantly reduced secreted PCSK9 and increased cell-surface LDLR expression. On the other hand, NRDC overexpression in cultured hepatocytes significantly increased secreted PCSK9 and lowered cell-surface LDLR expression. Thus, NRDC in murine hepatocytes appears to play key roles in cholesterol homeostasis, although the precise molecular mechanisms remain to be determined.

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Nardilysin controls intestinal tumorigenesis through HDAC1/p53–dependent transcriptional regulation

Cited by 10 publications

References 39 publications

Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma

Epigenetic Alterations Upstream and Downstream of p53 Signaling in Colorectal Carcinoma

Nardilysin controls cardiac sympathetic innervation patterning through regulation of p75 neurotrophin receptor

Deficiency of Nardilysin in the Liver Reduces Serum Cholesterol Levels

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